Growth of the long bones, initiated by paracrine factors, is engendered by recruiting chondrocytes from more primitive cells (mesenchymal cells of bone marrow) adjacent to the growth plate of the epiphysis. Linear growth in childhood results from endochondral ossification in the growth plate of long bones and vertebrae. For normal growth to occur there must be a co-ordinated sequence of steps involving (i) proliferation of chondrocytes within the growth plate, (ii) differentiation of chondrocytes to larger cells (hypertrophic phase) which lay down an extracellular matrix, (iii) apoptosis (programmed cell death) and mineralisation of matrix (ossification).
The proliferation phase is crucial to the growth process, and is regulated in health largely by paracrine and hormonal factors including growth hormone (GH), IGF-1, thyroxine and glucocorticoids. In humans, growth ceases, with disappearance of growth plates, after pubertal secretion of sex steroids which reduce chondrocyte proliferation and result in epiphyseal fusion.
Little is known of the paracrine factors affecting chondrocyte proliferation within the growth plate.
Of the many other factors present in growth plate tissues, and known to be important for normal growth, none has been shown to circulate in the blood at quantities sufficient for monitoring growth plate activity.
Indirect markers exist for assessing the growth potential in a subject. It is known, for example, in the art that a crude estimation of skeletal maturation (and hence potential for further growth) can be determined by a clinician examining an x-ray of the left wrist of a human. This provides an assessment of “bone age”.
Unfortunately, the above process is highly subjective. Accuracy in measuring bone age is often dependent upon the skill and experience of the clinician.
Additionally, assessment of bone age using this technique cannot be used to detect short term changes in growth plate activity. This inability is particularly problematic in acute illness or during drug or other interventions, where influences on bone development could become an important indicator of progression of the disease or treatment. For example, overmedication of a patient with corticosteroids is known to adversely affect skeletal growth. An early indication of this would be useful to clinicians.
A need exists for an objective determination of skeletal growth in a subject. It would be desirable if such a determination involved the direct measurement of a circulating marker, changes in which correlated with changes to the rate of skeletal development in growing human infants and children. Such a determination would, for example, enable clinicians to objectively and more rapidly detect the overall rate of skeletal development or short-term changes in skeletal development in patients, and to amend treatment regimens to minimise any adverse effects on skeletal growth and development, if necessary.
It is an object of the present invention to go some way towards fulfilling this need and/or to at least provide the public with a useful choice.